Interactions of anti-COVID-19 drug candidates with hepatic transporters
may cause liver toxicity and affect drug metabolism
Background: Transporters in the human liver play a major role in the
metabolism of endo- and xenobiotics, as well as of pharmaceutical
agents. Drugs and metabolites are extruded into the bile through the
apical, canalicular membrane of the hepatocytes, while transporters in
the basolateral membrane either promote the uptake or perform an
extrusion of various compounds into the venous blood stream.
Experimental Approach: In the present work we have examined the in vitro
interactions of some key repurposed drugs advocated to treat COVID-19
(lopinavir, ritonavir, ivermectin, remdesivir and favipiravir), with the
relevant key transporters in the hepatocytes. These transporters
included the ABCB11/BSEP, ABCC2/MRP2, and MATE1 in the canalicular
membrane, as well as ABCC3/MRP3, ABCC4/MRP4, OCT1, OATP1B1, OATP1B3, and
NTCP, residing in the basolateral membrane. Key Results: Lopinavir and
ritonavir in low micromolar concentrations inhibited the ABCB11/BSEP and
MATE1 exporters, as well as the OATP1B1/1B3 uptake transporters.
Ritonavir had a similar inhibitory pattern, also inhibiting OCT1.
Remdesivir strongly inhibited ABCC4/MRP4, OATP1B1/1B3, MATE1 and OCT1.
Thus, these agents may cause severe drug-drug interactions and
drug-induced liver injury. Favipiravir had no significant effect on any
of the transporters examined. Conclusion and Implications: Since both
general drug metabolism and drug-induced liver toxicity are strongly
dependent on the functioning of these transporters, the variable
interactions reported here may have important clinical relevance in the
drug treatment of this viral disease and the existing co-morbidities.